The major neurodegenerative disorders display a high degree of selective vulnerability in regard to the distribution of pathologic lesions. This selective vulnerability is apparent in the disease-related profile of neuronal loss, and degeneration of specific pathways. For example, in Alzheimer's disease (AD), the distribution of pathologic profiles and cell loss suggest that the cells of origin and circuits that comprise certain parahippocampal projections and corticocortical circuits in neocortex are devastated in AD, whereas many other elements of cortical circuitry are resistant to pathology. Patterns of selective vulnerability in the neocortex offer important clues as to which cortical circuits are compromised in a given disease, but our ability to relate such patterns to potential cellular or molecular pathogenetic mechanisms is greatly hampered by our lack of data correlating biochemical phenotype with connectivity in the primate neocortex. This proposal is designed to provide such information on the corticocortical projections in the monkey. We have demonstrated that the pyramidal cells that furnish corticocortical projections are not homogeneous in regard to biochemical phenotype and/or morphology and thus, by our criteria do not represent a uniform cell type. We hypothesize that both the cytoskeletal and neurotransmitter profiles of these neurons will be a crucial characteristic of their biochemical phenotype and will relate systematically to their connectivity patterns. For example, specific corticocortically projecting neurons win be characterized as to their content of neurofilament and microtubule-associated proteins, as well as whether or not they use glutamate as a neurotransmitter, or contain receptors for glutamate, acetylcholine, or GABA and if so, the precise dendritic distribution of each receptor will be determined. In addition, die precise distribution of chemically identified afferents to corticocorically projecting neurons will be determined. Techniques that combine retrograde transport, immunohistochemistry and intracellular loading will be used to characterize several different classes of corticocortically projecting neurons. By considering location, connectivity (synaptic inputs and efferent target), morphology, and biochemical phenotype, subtypes of corticocortically projecting cells can be defined and their relative contribution to a given corticocortical projection can be determined. We predict that the comprehensive profile Of a given cell, and in turn, a given projection, will be strongly related to its role in normal cortical function and to its vulnerability in AD or other neurodegenerative disorders. If we can pinpoint the elements of the biochemical and anatomic phenotype that are most clearly linked to differential cellular vulnerability in AD, then we will be one step closer to developing means of protecting those neurons that degenerate in AD. The protection of these neurons must be the paramount goal in developing a strategy for the management of AD, since prevention of a neurodegenerative disease is much more likely to be achievable than the development of a cure.